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Granulocyte macrophage colony-stimulating factor

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Title: Granulocyte macrophage colony-stimulating factor  
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Subject: Jennerex, Immunostimulant, Colony-stimulating factor, Growth factor, Granulocyte colony-stimulating factor
Collection: Cytokines, Drugs Acting on the Blood and Blood Forming Organs, Growth Factors
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Granulocyte macrophage colony-stimulating factor

Colony stimulating factor 2 (granulocyte-macrophage)
PDB rendering based on 2gmf
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; GMCSF
External IDs GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search
Granulocyte-macrophage colony-stimulating factor
three-dimensional structure of recombinant human granulocyte-macrophage colony-stimulating factor
Identifiers
Symbol GM_CSF
Pfam PF01109
Pfam clan CL0053
InterPro IPR000773
PROSITE PDOC00584
SCOP 2gmf
SUPERFAMILY 2gmf
Granulocyte macrophage colony-stimulating factor
Systematic (IUPAC) name
Human granulocyte macrophage colony stimulating factor
Identifiers
CAS Registry Number  Y
ATC code L03
DrugBank  N
Chemical data
Formula C639H1006N168O196S8
Molecular mass 14434.5 g/mol
 N   

Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, NK cells, endothelial cells and fibroblasts that functions as a cytokine. The pharmaceutical analogs of naturally occurring GM-CSF are called sargramostim and molgramostim.

Contents

  • Function 1
  • Genetics 2
  • Glycosylation 3
  • Medical use 4
    • Sargramostim 4.1
    • Rheumatoid arthritis 4.2
  • See also 5
  • References 6
  • External links 7

Function

GM-CSF is a monomeric glycoprotein that functions as a cytokine - it is a white blood cell growth factor.[1] GM-CSF stimulates stem cells to produce granulocytes (neutrophils, eosinophils, and basophils) and monocytes. Monocytes exit the circulation and migrate into tissue, whereupon they mature into macrophages and dendritic cells. Thus, it is part of the immune/inflammatory cascade, by which activation of a small number of macrophages can rapidly lead to an increase in their numbers, a process crucial for fighting infection.

GM-CSF signals via signal transducer and activator of transcription, STAT5.[2] In macrophages, it has also been shown to signal via STAT3. The cytokine activates macrophages to inhibit fungal survival. It induces deprivation in intracellular free zinc and increases production of reactive oxygen species that culminate in fungal zinc starvation and toxicity.[3] Thus, GM-CSF facilitates development of the immune system and promotes defense against infections.

GM-CSF also plays a role in embryonic development by functioning as an embryokine produced by reproductive tract.[4]

Genetics

The human gene has been localized to a cluster of related genes at chromosome region 5q31, which is known to be associated with interstitial deletions in the 5q- syndrome and acute myelogenous leukemia. Genes in the cluster include those encoding interleukins 4, 5, and 13.[5]

Glycosylation

Human granulocyte macrophage colony-stimulating factor is glycosylated in its mature form.

Medical use

GM-CSF is manufactured using recombinant DNA technology and is marketed as a protein therapeutic called molgramostim or, when the protein is expressed in yeast cells, sargramostim. It is used as a medication to stimulate the production of white blood cells and thus prevent neutropenia following chemotherapy.[6]

GM-CSF has also recently been evaluated in clinical trials for its potential as a vaccine adjuvant in HIV-infected patients. The preliminary results have been promising[7] but GM-CSF is not presently FDA-approved for this purpose.

Sargramostim

Sargramostim, recombinant yeast-derived GM-CSF developed at Immunex (now Amgen) and first given to six humans in 1987 as part of a compassionate-use protocol for the victims of cesium irradiation from the Goiânia accident.[8] It was originally developed by Immunex. When Amgen bought Immunex, sargramostim was divested to Berlex, a US subsidiary of Schering AG. Berlex was acquired by Bayer in 2006, and Bayer sold the franchise to Genzyme in 2009, which was subsequently acquired by Sanofi.[9] Its use was approved by U.S. Food and Drug Administration for acceleration of white blood cell recovery following autologous bone marrow transplantation in patients with non-Hodgkin's lymphoma, acute lymphocytic leukemia, or Hodgkin's disease in March 1991.[10] In November 1996, the FDA also approved sargramostim for treatment of fungal infections and replenishment of white blood cells following chemotherapy.[11]

Rheumatoid arthritis

GM-CSF is found in high levels in joints with rheumatoid arthritis and blocking GM-CSF may reduce the inflammation or damage. Some drugs (e.g. MOR103) are being developed to block GM-CSF.[12]

See also

References

  1. ^ Francisco-Cruz A, Aguilar-Santelises M, Ramos-Espinosa O, Mata-Espinosa D, Marquina-Castillo B, Barrios-Payan J, Hernandez-Pando R (Jan 2014). "Granulocyte-macrophage colony-stimulating factor: not just another haematopoietic growth factor". Medical Oncology 31 (1): 774.  
  2. ^ Voehringer D (Oct 2012). "Basophil modulation by cytokine instruction". European Journal of Immunology 42 (10): 2544–50.  
  3. ^ Subramanian Vignesh K, Landero Figueroa JA, Porollo A, Caruso JA, Deepe GS (Oct 2013). "Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival". Immunity 39 (4): 697–710.  
  4. ^ Hansen PJ, Dobbs KB, Denicol AC (Sep 2014). "Programming of the preimplantation embryo by the embryokine colony stimulating factor 2". Animal Reproduction Science 149 (1-2): 59–66.  
  5. ^ "Entrez Gene: CSF2 colony stimulating factor 2 (granulocyte-macrophage)". 
  6. ^ Vacchelli E, Eggermont A, Fridman WH, Galon J, Zitvogel L, Kroemer G, Galluzzi L (Jul 2013). "Trial Watch: Immunostimulatory cytokines". Oncoimmunology 2 (7): e24850.  
  7. ^ Breitbach CJ, Burke J, Jonker D, Stephenson J, Haas AR, Chow LQ, Nieva J, Hwang TH, Moon A, Patt R, Pelusio A, Le Boeuf F, Burns J, Evgin L, De Silva N, Cvancic S, Robertson T, Je JE, Lee YS, Parato K, Diallo JS, Fenster A, Daneshmand M, Bell JC, Kirn DH (Sep 2011). "Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans". Nature 477 (7362): 99–102.  
  8. ^ Schmeck HM (1987-11-02). "Radiation Team Sent to Brazil Saves Two With a New Drug". New York Times. Retrieved 2012-06-20. 
  9. ^ Stewart Lyman for Xcocomy. June 11, 2010 Biotech Drug Discovery in Seattle: A Look Back
  10. ^ "Approval Summary for sargramostim". Oncology Tools. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. 1991-03-05. Archived from the original on 2007-09-29. Retrieved 20 September 2009. 
  11. ^ "Newly Approved Drug Therapies (179): Leukine (sargramostim), Immunex". CenterWatch. Retrieved 2008-10-12. 
  12. ^ Deiß A, Brecht I, Haarmann A, Buttmann M (Mar 2013). "Treating multiple sclerosis with monoclonal antibodies: a 2013 update". Expert Review of Neurotherapeutics 13 (3): 313–35.  

External links

  • Official gentaur web site
  • Official Leukine web site
  • Granulocyte-Macrophage Colony-Stimulating Factor at the US National Library of Medicine Medical Subject Headings (MeSH)
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